{"gene":"PACS2","run_date":"2026-06-14T07:33:11","timeline":{"discoveries":[],"current_model":"Parse failed"},"narrative":{"mechanistic_narrative":"No mechanistic discoveries found in literature.","teleology":[],"mechanism_profile":null},"prefetch_data":{"uniprot":{"accession":"Q86VP3","full_name":"Phosphofurin acidic cluster sorting protein 2","aliases":["PACS1-like protein"],"length_aa":889,"mass_kda":97.7,"function":"Multifunctional sorting protein that controls the endoplasmic reticulum (ER)-mitochondria communication, including the apposition of mitochondria with the ER and ER homeostasis. In addition, in response to apoptotic inducer, translocates BIB to mitochondria, which initiates a sequence of events including the formation of mitochondrial truncated BID, the release of cytochrome c, the activation of caspase-3 thereby causing cell death. May also be involved in ion channel trafficking, directing acidic cluster-containing ion channels to distinct subcellular compartments","subcellular_location":"Endoplasmic reticulum; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q86VP3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PACS2","classification":"Not Classified","n_dependent_lines":14,"n_total_lines":1208,"dependency_fraction":0.011589403973509934},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PACS2","total_profiled":1310},"omim":[{"mim_id":"618067","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 66; DEE66","url":"https://www.omim.org/entry/618067"},{"mim_id":"610423","title":"PHOSPHOFURIN ACIDIC CLUSTER SORTING PROTEIN 2; PACS2","url":"https://www.omim.org/entry/610423"},{"mim_id":"607492","title":"PHOSPHOFURIN ACIDIC CLUSTER SORTING PROTEIN 1; PACS1","url":"https://www.omim.org/entry/607492"},{"mim_id":"308350","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 1; DEE1","url":"https://www.omim.org/entry/308350"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":95.7},{"tissue":"skeletal muscle","ntpm":31.6}],"url":"https://www.proteinatlas.org/search/PACS2"},"hgnc":{"alias_symbol":["KIAA0602"],"prev_symbol":["PACS1L"]},"alphafold":{"accession":"Q86VP3","domains":[{"cath_id":"2.60.40.150","chopping":"23-179","consensus_level":"high","plddt":85.8853,"start":23,"end":179},{"cath_id":"-","chopping":"467-651","consensus_level":"high","plddt":91.363,"start":467,"end":651},{"cath_id":"2.60.200.40","chopping":"654-684_745-756_772-810_827-870","consensus_level":"medium","plddt":83.0145,"start":654,"end":870}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86VP3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86VP3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86VP3-F1-predicted_aligned_error_v6.png","plddt_mean":66.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PACS2","jax_strain_url":"https://www.jax.org/strain/search?query=PACS2"},"sequence":{"accession":"Q86VP3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86VP3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86VP3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86VP3"}},"corpus_meta":[{"pmid":"15692567","id":"PMC_15692567","title":"PACS-2 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Nephropathy.","date":"2022","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/35133431","citation_count":85,"is_preprint":false},{"pmid":"32673704","id":"PMC_32673704","title":"PACS-2: A key regulator of mitochondria-associated membranes (MAMs).","date":"2020","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/32673704","citation_count":78,"is_preprint":false},{"pmid":"31242668","id":"PMC_31242668","title":"The Multifunctional Sorting Protein PACS-2 Controls Mitophagosome Formation in Human Vascular Smooth Muscle Cells through Mitochondria-ER Contact Sites.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31242668","citation_count":75,"is_preprint":false},{"pmid":"18296443","id":"PMC_18296443","title":"HIV-1 Nef binds PACS-2 to assemble a multikinase cascade that triggers major histocompatibility complex class I (MHC-I) down-regulation: analysis using short interfering RNA and knock-out mice.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18296443","citation_count":73,"is_preprint":false},{"pmid":"25159152","id":"PMC_25159152","title":"The multifunctional sorting protein PACS-2 regulates SIRT1-mediated deacetylation of p53 to modulate p21-dependent cell-cycle arrest.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25159152","citation_count":69,"is_preprint":false},{"pmid":"19481529","id":"PMC_19481529","title":"Akt and 14-3-3 control a PACS-2 homeostatic switch that integrates membrane traffic with TRAIL-induced apoptosis.","date":"2009","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/19481529","citation_count":67,"is_preprint":false},{"pmid":"11274944","id":"PMC_11274944","title":"Effect of postoperative atrial fibrillation on length of stay after cardiac surgery (The Postoperative Atrial Fibrillation in Cardiac Surgery study [PACS(2)].","date":"2001","source":"The American journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/11274944","citation_count":65,"is_preprint":false},{"pmid":"30970236","id":"PMC_30970236","title":"PACS2 is required for ox-LDL-induced endothelial cell apoptosis by regulating mitochondria-associated ER membrane formation and mitochondrial Ca2+ elevation.","date":"2019","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30970236","citation_count":59,"is_preprint":false},{"pmid":"22496420","id":"PMC_22496420","title":"An interdomain binding site on HIV-1 Nef interacts with PACS-1 and PACS-2 on endosomes to down-regulate MHC-I.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/22496420","citation_count":58,"is_preprint":false},{"pmid":"29656858","id":"PMC_29656858","title":"A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis.","date":"2018","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29656858","citation_count":57,"is_preprint":false},{"pmid":"34836936","id":"PMC_34836936","title":"PACS-2 attenuates diabetic kidney disease via the enhancement of mitochondria-associated endoplasmic reticulum membrane formation.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34836936","citation_count":54,"is_preprint":false},{"pmid":"22645134","id":"PMC_22645134","title":"Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein-induced lysosomal translocation of proapoptotic effectors is mediated by phosphofurin acidic cluster sorting protein-2 (PACS-2).","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22645134","citation_count":47,"is_preprint":false},{"pmid":"26108729","id":"PMC_26108729","title":"The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26108729","citation_count":45,"is_preprint":false},{"pmid":"30415949","id":"PMC_30415949","title":"An Insulin-Responsive Sensor in the SIRT1 Disordered Region Binds DBC1 and PACS-2 to Control Enzyme Activity.","date":"2018","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/30415949","citation_count":42,"is_preprint":false},{"pmid":"39633391","id":"PMC_39633391","title":"PACS2/CPT1A/DHODH signaling promotes cardiomyocyte ferroptosis in diabetic cardiomyopathy.","date":"2024","source":"Cardiovascular diabetology","url":"https://pubmed.ncbi.nlm.nih.gov/39633391","citation_count":31,"is_preprint":false},{"pmid":"26943323","id":"PMC_26943323","title":"PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage.","date":"2016","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/26943323","citation_count":30,"is_preprint":false},{"pmid":"36481261","id":"PMC_36481261","title":"Ferulic acid attenuates high glucose-induced MAM alterations via PACS2/IP3R2/FUNDC1/VDAC1 pathway activating proapoptotic proteins and ameliorates cardiomyopathy in diabetic rats.","date":"2022","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/36481261","citation_count":27,"is_preprint":false},{"pmid":"24633224","id":"PMC_24633224","title":"Cellular inhibitor of apoptosis (cIAP)-mediated ubiquitination of phosphofurin acidic cluster sorting protein 2 (PACS-2) negatively regulates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cytotoxicity.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24633224","citation_count":27,"is_preprint":false},{"pmid":"35212819","id":"PMC_35212819","title":"PACS2-TRPV1 axis is required for ER-mitochondrial tethering during ER stress and lung fibrosis.","date":"2022","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/35212819","citation_count":26,"is_preprint":false},{"pmid":"36138342","id":"PMC_36138342","title":"PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease.","date":"2022","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/36138342","citation_count":26,"is_preprint":false},{"pmid":"37794057","id":"PMC_37794057","title":"PACS-2 deficiency aggravates tubular injury in diabetic kidney disease by inhibiting ER-phagy.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37794057","citation_count":24,"is_preprint":false},{"pmid":"30684285","id":"PMC_30684285","title":"Expanding the clinical spectrum associated with PACS2 mutations.","date":"2019","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30684285","citation_count":19,"is_preprint":false},{"pmid":"35865947","id":"PMC_35865947","title":"AKT/PACS2 Participates in Renal Vascular Hyperpermeability by Regulating Endothelial Fatty Acid Oxidation in Diabetic Mice.","date":"2022","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35865947","citation_count":13,"is_preprint":false},{"pmid":"36968068","id":"PMC_36968068","title":"Mitochondria-associated membrane protein PACS2 maintains right cardiac function in hypobaric hypoxia.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/36968068","citation_count":11,"is_preprint":false},{"pmid":"33369122","id":"PMC_33369122","title":"Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis.","date":"2020","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/33369122","citation_count":11,"is_preprint":false},{"pmid":"39173402","id":"PMC_39173402","title":"Renal denervation improves mitochondrial oxidative stress and cardiac hypertrophy through inactivating SP1/BACH1-PACS2 signaling.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39173402","citation_count":10,"is_preprint":false},{"pmid":"36188273","id":"PMC_36188273","title":"The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis.","date":"2022","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/36188273","citation_count":9,"is_preprint":false},{"pmid":"35770754","id":"PMC_35770754","title":"First reported case of an inherited PACS2 pathogenic variant with variable expression.","date":"2022","source":"Epileptic disorders : international epilepsy journal with videotape","url":"https://pubmed.ncbi.nlm.nih.gov/35770754","citation_count":7,"is_preprint":false},{"pmid":"31432119","id":"PMC_31432119","title":"MAP‑1B, PACS‑2 and AHCYL1 are regulated by miR‑34A/B/C and miR‑449 in neuroplasticity following traumatic spinal cord injury in rats: Preliminary explorative results from microarray data.","date":"2019","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/31432119","citation_count":7,"is_preprint":false},{"pmid":"34405643","id":"PMC_34405643","title":"[Early infantile epileptic encephalopathy caused by PACS2 gene variation: three cases report and literature review].","date":"2021","source":"Zhonghua er ke za zhi = Chinese journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/34405643","citation_count":6,"is_preprint":false},{"pmid":"40653022","id":"PMC_40653022","title":"PACS2 initiates foam cell formation in macrophages through the ROS-PPARγ-CD36 positive feedback loop.","date":"2025","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40653022","citation_count":5,"is_preprint":false},{"pmid":"34894068","id":"PMC_34894068","title":"Vein of Galen aneurysm, dilated cardiomyopathy, and slender habitus in a patient with a recurrent pathogenic variant in PACS2.","date":"2021","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/34894068","citation_count":5,"is_preprint":false},{"pmid":"35951762","id":"PMC_35951762","title":"Knockdown of circ_0002194 protects against oxidized low-density lipoprotein-induced cell damage via the regulation of the miR-637/PACS2 axis in human vascular endothelial cells.","date":"2022","source":"Interactive cardiovascular and thoracic surgery","url":"https://pubmed.ncbi.nlm.nih.gov/35951762","citation_count":5,"is_preprint":false},{"pmid":"29312533","id":"PMC_29312533","title":"Loss of PACS-2 delays regeneration in DSS-induced colitis but does not affect the ApcMin model of colorectal cancer.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29312533","citation_count":5,"is_preprint":false},{"pmid":"39031646","id":"PMC_39031646","title":"PACS-1 variant protein is aberrantly localized in Caenorhabditis elegans model of PACS1/PACS2 syndromes.","date":"2024","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39031646","citation_count":4,"is_preprint":false},{"pmid":"40775117","id":"PMC_40775117","title":"PACS2/PKCα/NOX4 pathway damaged the renal vascular endothelial barrier by promoting ROS production in diabetic nephropathy mice.","date":"2025","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40775117","citation_count":3,"is_preprint":false},{"pmid":"37189870","id":"PMC_37189870","title":"Long-Term Outcome of Neonatal Seizure with PACS2 Mutation: Case Series and Literature Review.","date":"2023","source":"Children (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37189870","citation_count":3,"is_preprint":false},{"pmid":"41190767","id":"PMC_41190767","title":"PACS-2 Mitigates NPSC Apoptosis and Intervertebral Disc Degeneration by Preserving MAM Integrity via the SP1/LRRK2/Mfn2 Axis.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41190767","citation_count":2,"is_preprint":false},{"pmid":"37064331","id":"PMC_37064331","title":"First Report of Mexican Patients with PACS1-Related Neurodevelopmental Disorder and Review of the PACS1-, PACS2-, and WDR37-Related Ophthalmological Manifestations.","date":"2022","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/37064331","citation_count":2,"is_preprint":false},{"pmid":"38545008","id":"PMC_38545008","title":"A missense variant in the PACS2 gene cause Epileptic Encephalopathy and seizures in Saudi family.","date":"2024","source":"Pakistan journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38545008","citation_count":1,"is_preprint":false},{"pmid":"40869285","id":"PMC_40869285","title":"AI-Based Facial Phenotyping Supports a Shared Molecular Axis in PACS1-, PACS2-, and WDR37-Related Syndromes.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40869285","citation_count":1,"is_preprint":false},{"pmid":"39911171","id":"PMC_39911171","title":"PACS2, PACS1, and VACTERL: A Clinical Overlap.","date":"2024","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/39911171","citation_count":1,"is_preprint":false},{"pmid":"38031819","id":"PMC_38031819","title":"PACS2 pathogenic variant associated with malformation of cortical development and epilepsy.","date":"2023","source":"Epileptic disorders : international epilepsy journal with videotape","url":"https://pubmed.ncbi.nlm.nih.gov/38031819","citation_count":1,"is_preprint":false},{"pmid":"38661085","id":"PMC_38661085","title":"The PACS-2 protein and trafficking motifs in CCHFV Gn and Gc cytoplasmic domains govern CCHFV assembly.","date":"2024","source":"Emerging microbes & infections","url":"https://pubmed.ncbi.nlm.nih.gov/38661085","citation_count":1,"is_preprint":false},{"pmid":"34625934","id":"PMC_34625934","title":"[Clinical and genetic analysis of PACS2 gene variant in two child patients with developmental and epileptic encephalopathy 66].","date":"2021","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34625934","citation_count":1,"is_preprint":false},{"pmid":"38540691","id":"PMC_38540691","title":"Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature.","date":"2024","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/38540691","citation_count":0,"is_preprint":false},{"pmid":"39738582","id":"PMC_39738582","title":"Understanding PACS2 syndrome's pathomechanism by studying E209K and E211K mutations.","date":"2024","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/39738582","citation_count":0,"is_preprint":false},{"pmid":"42104568","id":"PMC_42104568","title":"PACS2 Alleviates Sepsis-Induced Myopathy by Activating ERK-MAPK Signalling Pathway to Suppress ER-Phagy.","date":"2026","source":"Journal of cachexia, sarcopenia and muscle","url":"https://pubmed.ncbi.nlm.nih.gov/42104568","citation_count":0,"is_preprint":false},{"pmid":"41692703","id":"PMC_41692703","title":"Quercetin Alleviates Endothelial Dysfunction in Atherosclerosis by Inhibiting Ferroptosis Through PACS2/HMOX-1 Pathway.","date":"2026","source":"The American journal of Chinese medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41692703","citation_count":0,"is_preprint":false},{"pmid":"38712144","id":"PMC_38712144","title":"PACS-1 variant protein is aberrantly localized in C. elegans model of PACS1/PACS2 syndromes.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38712144","citation_count":0,"is_preprint":false},{"pmid":"42140577","id":"PMC_42140577","title":"Silencing PACS2 attenuates cardiac hypertrophy by inhibiting ferroptosis via activating SIRT1.","date":"2026","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/42140577","citation_count":0,"is_preprint":false},{"pmid":"41644764","id":"PMC_41644764","title":"MiR-499-5P/PACS2/TRPV1 Axis Maintains Mitochondrial Homeostasis and Left Ventricular Function after Extreme Cold Stress.","date":"2026","source":"Journal of cardiovascular translational research","url":"https://pubmed.ncbi.nlm.nih.gov/41644764","citation_count":0,"is_preprint":false},{"pmid":"41687826","id":"PMC_41687826","title":"PACS2 deficiency ameliorates hepatic steatosis via inhibition of the JNK signaling pathway in diabetic mice.","date":"2026","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41687826","citation_count":0,"is_preprint":false},{"pmid":"41917949","id":"PMC_41917949","title":"Macrophage FTO deficiency accelerates atherosclerosis via PACS2-mediated activation of the PPARγ lipid signaling pathway.","date":"2026","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41917949","citation_count":0,"is_preprint":false},{"pmid":"41962777","id":"PMC_41962777","title":"Crebanine attenuates copper neurotoxicity via PACS-2 upregulation and TXNIP/TRPV1 axis suppression.","date":"2026","source":"Neurotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/41962777","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":32199,"output_tokens":4806,"usd":0.084344,"stage1_stop_reason":"refusal"},"stage2":{"model":"","input_tokens":0,"output_tokens":0,"usd":0.0},"total_usd":0.084344,"stage1_batch_id":"msgbatch_015cW3C55o5xm8EPaM1UvcZR","stage2_batch_id":"msgbatch_018NDJHPntdYJzBohpB6hHKo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"PACS-2 controls the apposition of mitochondria with the ER; depletion of PACS-2 causes BAP31-dependent mitochondria fragmentation and uncoupling from the ER. PACS-2 also controls formation of ER lipid-synthesizing centers on mitochondria-associated membranes (MAM) and ER homeostasis. In response to apoptotic inducers, PACS-2 translocates Bid to mitochondria, initiating truncated Bid formation, cytochrome c release, and caspase-3 activation.\",\n      \"method\": \"siRNA knockdown, subcellular fractionation, confocal microscopy, apoptosis assays (cytochrome c release, caspase-3 activation), co-immunoprecipitation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (knockdown, fractionation, imaging, biochemical apoptosis assays) in a single rigorous study, widely replicated by subsequent work\",\n      \"pmids\": [\"15692567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PACS-2 sorts calnexin between the rough ER, MAM, and plasma membrane. Phosphorylation of calnexin cytosolic serines Ser554/564 by CK2 reduces calnexin binding to PACS-2, and a phosphomimic mutation (Ser554/564Asp) partially reproduces PACS-2 knockdown by increasing calnexin at the cell surface and reducing it at the MAM.\",\n      \"method\": \"PACS-2 siRNA knockdown, co-immunoprecipitation, phosphomimic mutagenesis, immunofluorescence/cell-surface biotinylation assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays combined with mutagenesis and quantitative localization assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18417615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HIV-1 Nef binds PACS-2 via its EEEE65 acidic cluster; this interaction targets Nef to the paranuclear/TGN region, enabling Nef PXXP75 to activate a TGN-localized Src family kinase (SFK), which phosphorylates ZAP-70 to recruit class I PI3K, assembling a multikinase cascade that drives MHC-I down-regulation. PACS-2 is also required for retrograde trafficking of the cation-independent mannose 6-phosphate receptor from early endosomes to the TGN.\",\n      \"method\": \"siRNA knockdown, Pacs-2−/− mouse splenocytes and embryonic fibroblasts (genetic knockout), co-immunoprecipitation, kinase assays, MHC-I surface FACS\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout phenocopies siRNA, multiple orthogonal biochemical and cell biological assays, mechanistic pathway dissected\",\n      \"pmids\": [\"18296443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PACS-2 is phosphorylated at Ser437 in vivo by Akt. Phospho-Ser437 binds 14-3-3 with high affinity, which represses PACS-2 apoptotic activity while enabling PACS-2 to mediate membrane cargo trafficking. TRAIL triggers Ser437 dephosphorylation, reprogramming PACS-2 to promote apoptosis. This phosphorylation state constitutes a molecular switch integrating cellular homeostasis with TRAIL-induced apoptosis.\",\n      \"method\": \"In vivo phosphorylation mapping, pharmacologic and genetic Akt inhibition, Pacs-2−/− mice (TRAIL-induced hepatocyte killing), 14-3-3 binding assays, cargo trafficking assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout, pharmacologic inhibition, and biochemical binding assays all converge; in vivo validation in mice\",\n      \"pmids\": [\"19481529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A previously unidentified cargo subsite on PACS-1 and PACS-2 interacts with a bipartite site on Nef formed by the EEEE65 acidic cluster and W113. This Nef–PACS interaction occurs on Rab5- (PACS-2 and PACS-1) or Rab7- (PACS-1)-positive endosomes; disrupting it prevents Nef from localizing to endosomal compartments and blocks MHC-I down-regulation.\",\n      \"method\": \"Bimolecular fluorescence complementation (BiFC), site-directed mutagenesis of Nef and PACS proteins, peripheral blood mononuclear cell MHC-I surface assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of interacting sites combined with live-cell BiFC and functional MHC-I readout; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22496420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRAIL induces recruitment of PACS-2 to DR5-positive endosomes where it forms a complex with Bim and Bax on lysosomal membranes. Recombinant PACS-2 binds Bim but not Bax in vitro; Bim knockdown blocks Bax recruitment. PACS-2-mediated Bim/Bax recruitment to lysosomes is required for lysosomal membrane permeabilization, cathepsin B release, and TRAIL-induced apoptosis.\",\n      \"method\": \"shRNA knockdown, co-immunoprecipitation, in vitro recombinant protein binding assay, confocal microscopy, lysosomal permeabilization assay, clonogenic survival assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding assay plus multiple cellular assays (co-IP, knockdown, functional readouts), single lab\",\n      \"pmids\": [\"22645134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PACS-2 shuttles from the cytoplasm to the nucleus, where it interacts with SIRT1 and directly inhibits SIRT1-catalyzed deacetylation of p53 in vitro. In PACS-2 knockdown cells and Pacs-2−/− thymocytes, p53 acetylation is reduced, blunting p21 (CDKN1A) induction and impairing p21-dependent cell-cycle arrest after DNA damage. SIRT1 inhibition or knockdown rescues these defects.\",\n      \"method\": \"In vitro SIRT1 deacetylation assay, PACS-2 knockdown/Pacs-2−/− mice thymocytes, co-immunoprecipitation (PACS-2–SIRT1), p53 acetylation immunoblot, p21 reporter/immunoblot, cell-cycle analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro enzymatic assay demonstrates direct inhibition; genetic knockout and siRNA knockdown phenocopy; multiple orthogonal methods\",\n      \"pmids\": [\"25159152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"cIAP-1 and cIAP-2 interact with PACS-2 in vivo (co-IP) and directly mediate K48-linked poly-ubiquitination of PACS-2 in a cell-free ubiquitination assay, leading to proteasomal degradation of PACS-2. Combined deletion of both cIAP-1 and cIAP-2 reduces PACS-2 ubiquitination, elevates PACS-2 levels, and sensitizes cells to TRAIL-induced lysosomal membrane permeabilization and apoptosis in a PACS-2-dependent manner.\",\n      \"method\": \"Cell-free ubiquitination assay, co-immunoprecipitation, c-Iap single and double knockout mouse hepatocytes, TRAIL apoptosis assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — cell-free ubiquitination assay (Tier 1) combined with genetic knockouts and co-IP; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24633224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PACS-2 co-localizes with ADAM17 on early endosomes and is required for recycling of internalized ADAM17 back to the cell surface; PACS-2 loss reduces ADAM17 cell-surface levels and ADAM17-dependent ErbB ligand shedding without affecting related proteases. Pacs2-deficient mice display significantly reduced phosphorylated EGFR and intestinal proliferation.\",\n      \"method\": \"Genome-wide siRNA screen, PACS-2 knockdown, ADAM17 cell-surface biotinylation, recycling assays, confocal co-localization, Pacs2−/− mouse intestinal analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide functional screen identification, knockdown trafficking assays, and in vivo genetic validation in knockout mice\",\n      \"pmids\": [\"26108729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PACS-2 promotes ATM-dependent NF-κB activation in response to DNA damage by interacting with ATM in the cytoplasm, driving Bcl-xL induction. Pacs-2−/− thymocytes show blunted Bcl-xL induction, increased mitochondrial outer membrane permeabilization, and accelerated apoptosis after DNA damage. PACS-2 is not required for TNF-α-induced NF-κB activation.\",\n      \"method\": \"Pacs-2−/− mouse thymocytes, co-immunoprecipitation (PACS-2–ATM), NF-κB reporter assays, Bcl-xL immunoblot, MOMP assays, apoptosis assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with clear phenotypic readout combined with co-IP to place PACS-2 in the ATM–NF-κB pathway; single lab, multiple methods\",\n      \"pmids\": [\"26943323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PACS-2 engages an insulin-responsive sensor in the SIRT1 N-terminal disordered region comprising an acidic cluster (AC) and a 3-helix bundle (3HB). DBC1 removes a distal N-terminal shield, permitting PACS-2 to engage the AC and transiently exposed helix 3 of the 3HB, disrupting its structure and inhibiting SIRT1 catalysis. The SIRT1 activator SRT1720 stabilizes the 3HB, protecting SIRT1 from PACS-2-mediated inhibition.\",\n      \"method\": \"NMR structural studies of SIRT1 NTR, in vitro binding and enzymatic assays, mutagenesis, pharmacologic STAC (SRT1720) rescue\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural validation plus in vitro enzymatic assays and mutagenesis; single lab with multiple orthogonal rigorous methods\",\n      \"pmids\": [\"30415949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A recurrent de novo PACS2 E209K missense variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR (cargo/furin-binding region) and client proteins, potentially disturbing cellular trafficking function. Functional studies confirmed this biochemical disruption.\",\n      \"method\": \"Functional cellular assays of autoregulatory domain–FBR interaction modulation in cells expressing wild-type vs. E209K PACS-2\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional assay described but limited methodological detail in abstract; replicated across 14 unrelated individuals with consistent genotype–phenotype correlation\",\n      \"pmids\": [\"29656858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PACS-2 knockdown impairs mitophagosome formation in vascular smooth muscle cells; increased MAM contacts and PACS-2-associated MAMs are observed upon atherogenic lipid stimulation. Disruption of MAM contacts by PACS-2 knockdown potentiates VSMC apoptosis rather than mitophagy-mediated survival.\",\n      \"method\": \"High-resolution confocal microscopy, proximity ligation assays (MAM contacts), PACS-2 siRNA knockdown, mitophagy flux assays, apoptosis assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — proximity ligation assays and knockdown with mitophagy/apoptosis readouts; single lab\",\n      \"pmids\": [\"31242668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ox-LDL promotes PACS2 localization to mitochondria and increases ER-mitochondria contacts (MAM formation). Silencing PACS2 inhibits ox-LDL-induced MAM formation, mitochondrial Ca2+ elevation, mitochondrial membrane potential loss, ROS production, cytochrome c release, and endothelial cell apoptosis.\",\n      \"method\": \"PACS2 siRNA knockdown, confocal microscopy (PACS2 mitochondrial localization), electron microscopy (MAM contacts), mitochondrial Ca2+ measurement, flow cytometry (apoptosis, ROS)\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct localization imaging combined with functional knockdown; single lab, multiple cellular readouts\",\n      \"pmids\": [\"30970236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PACS-2 binds BECN1 (Beclin-1) and mediates relocalization of BECN1 to the MAM, where it promotes mitophagosome formation. In vitro, PACS-2 overexpression in HK-2 cells alleviates excessive mitochondrial fission induced by high glucose by blocking mitochondrial recruitment of DRP1.\",\n      \"method\": \"Co-immunoprecipitation (PACS-2–BECN1), subcellular fractionation, confocal co-localization, PACS-2 overexpression and conditional knockout mice (proximal tubule-specific), electron microscopy (MAM), mitophagy assays\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP identifies BECN1 as binding partner, conditional knockout mouse phenotype validates in vivo, multiple orthogonal methods across genetic and cellular levels\",\n      \"pmids\": [\"35133431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PACS-2 interaction with TRPV1 (transient receptor potential cation channel V1) influences PACS2 protein levels; PACS2 levels are reduced by ER stress and in IPF alveolar epithelial cells. The PACS2-TRPV1 axis is required for ER-mitochondria tethering; TRPV1-modulating drug capsaicin restores PACS2 levels and reduces apoptosis in ER-stressed cells.\",\n      \"method\": \"PACS2 overexpression/Chop overexpression cell models, capsaicin (TRPV1 modulator) treatment, precision cut lung slices from IPF patients, ER-mitochondria proximity assays, apoptosis assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional rescue with TRPV1 modulator and ex vivo patient tissue; interaction implied but not directly demonstrated by co-IP in abstract\",\n      \"pmids\": [\"35212819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PACS-2 E209K (disease-associated mutation) exhibits a slower protein turnover rate relative to wild-type PACS-2, has increased association with 14-3-3ε, and increases susceptibility to staurosporine-induced apoptosis compared to wild-type.\",\n      \"method\": \"Cycloheximide chase assay, co-immunoprecipitation (14-3-3ε), staurosporine apoptosis assay in HCT116 cells expressing WT or E209K PACS-2\",\n      \"journal\": \"ACS omega\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — clear biochemical assays but single lab, single paper, focused on disease variant\",\n      \"pmids\": [\"36188273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\":","stage2_raw":"","audit_flag":{"gene":"PACS2","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"recall_miss","uniprot_band":"medium","rules_fired":"R5","issue":"R5: no narrative despite experimental UniProt FUNCTION (571 chars) and on-target evidence in corpus (34 on-target corpus titles)"},"evaluation":null}